Program Director/Principal Investigator (Last, First, Middle): Hennebold, Jon PHS 398/2590 (Rev. 11/07) Page Continuation Format Page ABSTRACT The long-term objective of this research is to define the mechanisms occurring within the primate corpus luteum (CL) that are critical for its development and regression. Evidence obtained from nonprimate species indicates that prostaglandins (PGs) regulate luteal structure-function, but their role in primate luteal physiology have not been defined. Recent preliminary data have demonstrated that the expression of PGE2 synthesis (prostaglandin-endoperoxide synthase 2 or PTGS2;microsomal PGE2 synthase-1 or PTGES) and signaling (PGE2 receptor 3 or PTGER3) components peak in the rhesus macaque CL through the period of its development. Moreover, expression of the PGE2 synthesizing and signaling components significantly decreased preceding the period of functional regression of the CL, which also coincided with increasing levels of PGF2_ receptor (PTGFR) expression. Thus, experiments will be performed to test the hypothesis that PGE2 actions are critical for primate luteal development, while PGF2_ serves as a critical intraluteal initiator and/or effector of luteolysis. Studies using rhesus macaques are proposed that will assess the role PGE2 signaling plays in the development of the primate CL (Aim 1) and evaluate whether PGF2_ signaling is required for the demise of the CL at the end of the luteal phase (Aim 2). Protocols blocking intraluteal PG synthesis via a PTGS2 selective inhibitor will determine their role in CL development. The ablation of PG synthesis in the developing CL will be combined with the restoration of PTGER3 signaling through the use of a selective PTGER3 agonist. The intraluteal delivery of a PTGFR antagonist prior to the onset of luteal regression will establish the role of PGF2_ in luteolysis. Daily concentrations of serum progesterone, first day of menses, and CL weight will be used to evaluate luteal function and lifespan. Histochemical markers of apoptotic, endothelial, and steroidogenic cells will be used for morphologic analysis of CL structure, while the expression of LH-regulated steroidogenic and angiogenic factors will be quantified to evaluate the relationship between PG signaling and luteal function. These studies will provide novel insight into the role of PG actions in luteal development and regression in primates. Such an understanding of PG involvement in the regulation of luteal structure-function may aid in our undestanding of infertility or other disorders associated with luteal dysfunction.

Public Health Relevance

In nonprimate species, lipid-derived prostaglandins regulate cellular activities involved in the development and regression of the corpus luteum, a transient endocrine gland required for the maintenance of pregnancy. Their role in the primate corpus luteum, however, has not been determined. The objective of this research, therefore, includes determining the role that prostaglandins play in regulating molecular and cellular processes necessary for the development, function, and regression of the primate corpus luteum. Moreover, this knowledge will likely provide insight into the etiology of various ovarian-dependent aspects of infertility related to luteal phase defects.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD042000-06
Application #
7579598
Study Section
Special Emphasis Panel (ZRG1-EMNR-D (03))
Program Officer
Taymans, Susan
Project Start
2009-07-27
Project End
2011-06-30
Budget Start
2009-07-27
Budget End
2010-06-30
Support Year
6
Fiscal Year
2009
Total Cost
$576,209
Indirect Cost
Name
Oregon Health and Science University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Edelman, Alison B; Jensen, Jeffrey T; Doom, Carmen et al. (2013) Impact of the prostaglandin synthase-2 inhibitor celecoxib on ovulation and luteal events in women. Contraception 87:352-7
Shaw, Kate A; Hennebold, Jon D; Edelman, Alison B (2013) Effect of a combined estrogen and progesterone oral contraceptive on circulating adipocytokines adiponectin, resistin and DLK-1 in normal and obese female rhesus monkeys. Contraception 88:177-82
Stouffer, Richard L; Bishop, Cecily V; Bogan, Randy L et al. (2013) Endocrine and local control of the primate corpus luteum. Reprod Biol 13:259-71
Bogan, Randy L; Debarber, Andrea E; Hennebold, Jon D (2012) Liver x receptor modulation of gene expression leading to proluteolytic effects in primate luteal cells. Biol Reprod 86:89
Bishop, C V; Bogan, R L; Hennebold, J D et al. (2011) Analysis of microarray data from the macaque corpus luteum; the search for common themes in primate luteal regression. Mol Hum Reprod 17:143-51
Peluffo, Marina C; Murphy, Melinda J; Baughman, Serena Talcott et al. (2011) Systematic analysis of protease gene expression in the rhesus macaque ovulatory follicle: metalloproteinase involvement in follicle rupture. Endocrinology 152:3963-74
Xu, Fuhua; Stouffer, Richard L; Muller, Jorg et al. (2011) Dynamics of the transcriptome in the primate ovulatory follicle. Mol Hum Reprod 17:152-65
Letra, A; Menezes, R; Fonseca, R F et al. (2010) Novel cleft susceptibility genes in chromosome 6q. J Dent Res 89:927-32
Hennebold, Jon D (2010) Preventing granulosa cell apoptosis through the action of a single microRNA. Biol Reprod 83:165-7
Edelman, Alison B; Jensen, Jeffrey T; Hennebold, Jon D (2010) A nonhormonal model for emergency contraception: prostaglandin synthesis inhibitor effects on luteal function and lifespan, a pilot study. Contraception 81:496-500

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